Neuro-inflammation is characterized by immune cell infiltration across the blood-brain barrier, a process instrumental in neuronal cell death. In neuro-inflammation the blood-brain barrier is also damaged and the consequences of activated lymphocytes on the integrity of the blood-brain barrier is not well characterized. Utilizing an blood-brain barrier model we demonstrate that endothelial cell viability and barrier integrity are directly altered following lymphocyte exposure. The effect of activated lymphocytes is cell number dependent, mostly mediated by direct contact, and is not associated with the pro-inflammatory cytokine TNF-alpha. For the successful treatment of neuro-inflammatory disease, intervention of this direct effect at the blood-brain barrier is warranted.